INTRODUCTION TO THE

IMMUNE SYSTEM

Mary Ann W.Tomeldan-Balataro,MD,DFM,FPCGM

 IMMUNE SYSTEM
- a collection of cells,and proteins that function to protect the
skin,respiratory passages,intestinal tract and other areas from foreign
antigens,such as microbes,viruses,cancer cells and toxins.
- 3 key properties:
1. a highly diverse repertoire of antigen receptors that enables
recognition of a nearly infinite range of pathogens.
2. immune memory---to mount rapid recall immune responses
3. immunologic tolerance---to avoid immune damage to normal self-
tissues.
*** the anti-microbial defense function of the immune system is
essential for our ability to survive in an environment that is teeming
w/ potentially deadly microbes. however, immune responses are also
capable of causing damage.
*common dses are caused by uncontrolled or excessive
immune responses---RA,asthma,glomerulonephritis,
IBD,etc.
 IMMUNE SYSTEM
Innate Immunity
- ancient immune recognition
system of host cells bearing
germ line–encoded pattern
recognition receptors (PRRs)
that recognize pathogens and
trigger a variety of mechanisms
of pathogen elimination.
- refers to nonspecific defense
mechanisms that come into
play immediately or within
hours of an antigen's
appearance in the body
Adaptive Immunity
- Immune responses by these cells
are based on specific antigen
recognition by clonotypic
receptors that are products of
genes that rearrange during
development and throughout
the life of the organism.
(The antigen first must be
processed and recognized.)
* Once an antigen has been recognized,
the adaptive immune system creates
an army of immune cells specifically
designed to attack that antigen.
 Innate Immunity
- These mechanisms include physical Adaptive Immunty
barriers such as skin, chemicals in the
blood, and immune system cells that - refers to antigen-specific
attack foreign cells in the body. immune response.
- The innate immune response is
activated by chemical properties of - more complex than the
the antigen. innate.
- Cells of the innate immune system - also includes a "memory"
include natural killer cell that makes future
lymphocytes, monocytes/
responses against a
macrophages, dendritic cells,
neutrophilsbasophils, specific antigen more
eosinophils, tissue mast cells, and efficient
epithelial cells
 Definition of Terms:
*Antibody - B cell–produced molecules encoded by genes that
rearrange during B cell development consisting of immunoglobulin
heavy and light chains that together form the central component of the
B cell receptor for antigen.
-can exist as B cell–surface antigen-recognition molecules or as
secreted molecules in plasma and other body fluids.
*Antigens - foreign or self-molecules that are recognized by the
adaptive and innate immune systems resulting in immune cell
triggering, T cell activation, and/or B cell antibody production.
*Antimicrobial peptides —small peptides <100 amino acids in
length that are produced by cells of the innate immune system
and have anti-infectious agent activity.
*Apoptosis —the process of p rogrammed cell death whereby
signaling through various “death receptors” on the surface of cells
[e.g., tumor necrosis factor (TNF) receptors, CD95] leads to a
signaling cascade that involves activation of the caspase family of
molecules and leads to DNA cleavage and cell death.
*Autoimmune diseases —diseases such as SLE and RA in which
cells of the adaptive immune system such as autoreactive T and B
cells become overreactive and produce self-reactive T cell and
antibody responses.
* Autoinflammatory diseases —hereditary disorders such as hereditary
periodic fevers (HPFs) characterized by recurrent episodes
of severe inflammation and fever due to mutations in controls
of the innate inflammatory response.
*B cell receptor for antigen - complex of surface molecules that
rearrange during postnatal B cell development, made up ofsurface
immunoglobulin (Ig) and associated Ig αβ chain molecules
that recognize nominal antigen via Ig heavy- and light-chain
variable regions, and signal the B cell to terminally differentiate
to make antigen-specific antibody.
*B lymphocytes - bone marrow–derived or bursal-equivalent
lymphocytes that express surface immunoglobulin (the B cell
receptor for antigen) and secrete specific antibody after interaction
with antigen.
* Chemokines —soluble molecules that direct and determine
immune cell movement and circulation pathways.
*Complement - cascading series of plasma enzymes and effector
proteins whose function is to lyse pathogens and/or target them
to be phagocytized by neutrophils and monocyte/macrophage
lineage cells of the reticuloendothelial system.
*Co-stimulatory molecules —molecules of antigen-presenting cells
(such as B7-1 and B7-2 or CD40) that lead to T cell activation
when bound by ligands on activated T cells (such as CD28 or
CD40 ligand).
*Cytokines - soluble proteins that interact with specific cellular
receptors that are involved in the regulation of the growth and
activation of immune cells and mediate normal and pathologic
inflammatory and immune responses.
*Dendritic cells —myeloid and/or lymphoid lineage antigenpresenting
cells of the adaptive immune system.
- are key initiators both of innate immune responses via cytokine
production and of adaptive immune responses via presentation of
antigen to T lymphocytes.
*Inflammasome - large cytoplasmic complexes of intracellular
proteins that link the sensing of microbial products and cellular
stress to the proteolytic activation of interleukin (IL)-1β and
IL-18 inflammatory cytokines.
***Activation of molecules in the inflammasome is a key step in the
response of the innate immune system for intracellular recognition of
microbial and other danger signals in both health and pathologic
states.
* Large granular lymphocytes - lymphocytes of the innate immune
system with azurophilic cytotoxic granules that have natural
killer cell activity capable of killing foreign and host cells with
few or no self–major histocompatibility complex (MHC) class I
molecules
*Natural killer cells - large granular lymphocytes that kill target
cells expressing few or no human leukocyte antigen (HLA) class I
molecules, such as malignantly transformed cells and virally
infected cells.
*Natural killer (NK) T cells —innate-like lymphocytes that use an
invariant T cell receptor (TCR)-α chain combined with a limited
set of TCR-β chains and coexpress receptors commonly found
on NK cells. NK T cells recognize lipid antigens of bacterial,
viral, fungal, and protozoal infectious agents.
*Pathogen-associated molecular patterns (PAMPs)—Invariant
molecular structures expressed by large groups of microorganisms
that are recognized by host cellular pattern recognition
receptors in the mediation of innate immunity.
*Pattern recognition receptors (PRRs)—germ line–encoded
receptors expressed by cells of the innate immune system that
recognize pathogen-associated molecular patterns.
* Polyreactive natural antibodies - preexisting low-affinity antibodies produced by
innate B cells that cross-react with multiple antigens and are available at the time
of infection to bind to and coat the invading pathogen and harness innate
responses to slow the infection until an adaptive high-affinity protective antibody
response can be made.
* T cell receptor (TCR) for antigen —complex of surface molecules that rearrange
during postnatal T cell development made up of clonotypic TCR-α and -β chains
that are associated with the CD3 complex composed of invariant γ, δ, ε, ζ, and η
chains.
* T cells - thymus-derived lymphocytes that mediate adaptive cellular immune
responses including T helper, T regulatory, and cytotoxic T lymphocyte effector
cell functions.
* Tolerance - B and T cell nonresponsiveness to antigens that results from encounter
with foreign or self-antigens by B and T lymphocytes in the absence of expression
of antigen-presenting cell co-stimulatory molecules.
 INNATE IMMUNE SYSTEM

- represents the first line of defense to an intruding pathogen.

- an antigen-independent(non-specific) defense mechanism that is
used by the host immediately or within hours of encountering an
antigen.
- primary function: recruitment of immune cells to sites of
infection and inflammation through the production of
cytokines---leads to the release of antibodies and other proteins
and glycoproteins w/c activate the complement system.
- promotes clearance of dead cells or antibody complexes and
removes foreign substances present in organs,tissues,blood, and
lymph.
- can also activate the adaptive immune respone through a process
known as antigen presentation.
Major Components of the Innate Immune System
a) Pattern Recognition Receptors ( PRR)
- are a primitive part of the immune system
- They are proteins expressed by cells of the innate immune
system to identify pathogen-associated molecular patterns
(PAMPs), which are associated with microbial pathogens or
cellular stress, as well as damage-associated molecular
patterns (DAMPs), which are associated with cell
components released during cell damage.
***The microbe-specific molecules that are recognized by a
given PRR are called pathogen-associated molecular
patterns (PAMPs), include:
- bacterial carbohydrates (such as lipopolysaccharide or
LPS, mannose)
 - nucleic acids (such as bacterial or viral DNA or RNA)
- bacterial peptides (flagellin, ax21),
- peptidoglycans and lipoteichoic acids (from Gram positive
bacteria),
- N-formylmethionine,
- lipoproteins and fungal glucans.

*Endogenous stress signals are called danger-associated molecular

patterns (DAMPs) and include uric acid.
PRRs are classified according to their ligand specificity, function,
localization and/or evolutionary relationships.
On the basis of function, PRRs may be divided into endocytic PRRs or
signaling PRRs.
1. Signaling PRRs include the large families of membrane-bound Toll-
like receptors and cytoplasmic NOD-like receptors.

2. Endocytic PRRs promote the attachment, engulfment and

destruction of microorganisms by phagocytes, without relaying an
intracellular signal.
These PRRs recognize carbohydrates and include mannose receptors
of macrophages, glucan receptors present on all phagocytes and
scavenger receptors that recognize charged ligands, are found on all
phagocytes and mediate removal of apoptotic cells.
toll-like receptors (TLRs)
- play a major role in innate immunity and the induction of adaptive
immunity.
The binding of a microbial molecule to its TLR transmits a signal to the cell's
nucleus inducing the expression of genes coding for the synthesis of
intracellular regulatory molecules called cytokines. The cytokines, in turn,
bind to cytokine receptors on other defense cells.
Many of the TLRs, especially tht that bind to bacterial and fungal cell wall
components stimulate those transcription and translation of cytokines such
as interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha), and
interleukin-8 (IL-8) that trigger innate immune defenses such as
inflammation, fever, and phagocytosis in order to provide an immediate
response against the invading microorganism.
Most of the TLRs that bind to viral components trigger the synthesis of
cytokines called interferons that block viral replication within infected
host cells.
Cytokines such as interleukin-6 (IL-6) that promotes B-lymphocyte activity
and interleukin-12 that promotes T-lymphocyte activity are also produced.
NOD-like receptor (nucleotide-binding oligomerization domain
receptors
-are intracellular sensors of PAMPs that enter the cell via phagocytosis
or pores and DAMPs that are associated with cell stress.
- They are part of pattern recognition receptors and play key roles in
regulation of innate immune response.
*** NLRs can cooperate with Toll-like receptors and regulate
inflammatory and apoptotic response---- lymphocytes,
macrophages, dendritic cells and also in nonimmune cells, ex.
epithelium.
* NLRs ---trigger---form large cytoplasmic complexes--
inflammasomes-aggregates of moleculesincluding NOD-like
receptor pyrin (NLRP) proteins that are members of the NLR family
Inflammasomes activate inflammatory caspases and IL-1β in the
presence of nonbacterial danger signals (cell stress) and bacterial
PAMPs.
Mutations in inflammasome proteins can lead to chronic inflammatio in
a group of periodic febrile diseases called autoinflammatory syndromes
b. EFFECTOR CELLS OF INNATE IMMUNITY
1. Monocytes-Macrophages
- arise from precursor cells within bone marrow and circulate with
a half-life ranging from 1 to 3 days.
* monocytes leave the peripheral circulation by marginating in
capillaries and migrating into a vast extravascular pool.
*tissue macrophages arise from monocytes.
 Monocyte-macrophages

- first line of defense associated with innate immunity and ingest and
destroy microorganisms through the release of toxic products such as
hydrogen peroxide (H 2 O 2 ) and nitric oxide (NO).
- produce inflammatory mediators -prostaglandins,leukotrienes,PAF,
cytokines---IL1,TNF-α,IL-6, IL-12 and chemokines.
* undergo programmed cell death or apoptosis.

Major role:
- phagocytose and kill bacteria
- produce antimicrobial peptides
- bind ( LPS)
- produce inflammatory cytokines
2. Dedritic Cells
- are antigen-presenting cells, (also known as accessory cells) of the
mammalian immune system.
- main function is to process antigen material and present it on the cell
surface to the T cells of the immune system.
- They act as messengers between the innate and the adaptive immune
systems.
- subsets: a) myeloid DCs - Most similar to monocytes.
Two types: 1. Instertitial Dcs - producers of IL-12 and IL-10
- located in T cell zones of lymphoid organs,
circulate in blood, present in interstices of the
lung,heart and kidney.

2. Langerhans DCs producers of IL-12.

- located in T-cell zones --- lymph nodes, skin epithelia,thymic
medulla.
- also circulate in blood.
 **** major role in adaptive immunity
* Insterstitial Dcs are potent activators of macrophage and mature
Dcs to phagocytose invading pathogens and present pathogen
antigens to T and B cell.

b) plasmacytoid DCs - produce large amounts of inteferon-α (IFN-α)

- has antitumor and antiviral activity
- found in T cell zones of lymphoid organs
- circulate in blood

role in adaptive immunity:

- IFN-α --- a potent activator of macrophage and mature Dcs to
pagocytose invading pathogens and present pathogen antigens to T
and B cells.
* maturation of DCs is regulated through cell-to-cell contact and soluble
factors
* attract immune effectors through secretion of chemokines.
* contact w/ bacterial products,viral CHONs or host CHONs---released
as danger signals from distressed host cells
and
infectious agent molecules bind to various TLRs
activate DCs

release cytokines and chemokines that drive cells of innate

immune system
become activated
recruit T and B cells of the adaptive immune system to respond.
3. Natural killer (NK) cells or large granular
lymphocytes(LGLs)

- kill foreign and host cells that have low levels of MHC+ self
peptides.
* A cell that can react against and destroy another cell without
prior sensitization to it.
* part of our first line of defense against cancer cells and virus-
infected cells.
NK cells are small lymphocytes that originate in the bone marrow
and develop without the influence of the thymus.
An NK cell attaches to a target cell, releases chemicals that breach
its cell wall, and causes it to lyse (break up).

Role in adaptive immunity: produce TNF-α and IFN-ϒ.

* CD3 + invariant T cell receptor alpha chains

Natural Killer T Cells

- recognize lipid antigens of intracellular bacteria such as
Mycobacterium tuberculosis by Cd1 moleules and kill host cells
infected w intracellular bacteria.

Major role in adaptive immunty: produce IL-4 to recruit T 2 helper T

cell responses, IgG1 and IgE production.
4. Neutrophils (granulocytes)
- most abundant (40% to 75%) type of white blood cells in mammals
and form an essential part of the innate immune system.
- They are formed from stem cells in the bone marrow.
- They form part of the polymorphonuclear cell family (PMNs)
together with basophils and eosinophils.
- type of phagocyte and are normally found in the bloodstream.
* acute phase of inflammation, particularly as a result of bacterial
infection, environmental exposure, and some cancers,
--- neutrophils are one of the first-responders of inflammatory cells
to migrate towards the site of inflammation.
They migrate through the blood vessels, then through interstitial
tissue, following chemical signals such as Interleukin-8 (IL-8), C5a,
fMLP and Leukotriene B4 in a process called chemotaxis.
They are the predominant cells in pus, accounting for its
whitish/yellowish appearance.

****hallmark of acute inflammation

- major role--- phagocytose and kill bacteria
--- produce antimicrobial peptides

- in adaptive immunity-- produce nitric oxide synthase and nitric

oxide-- w/c inhibit apoptosis in lymphocytes and can prolong
adaptive immune responses.

***role in disease
- Neutropenia---Low neutrophil counts
- can be congenital (genetic disorder) or it can develop later, as in
the case of aplastic anemia or some kinds of leukemia.
It can also be a side-effect of medication, most prominently
chemotherapy.
Neutropenia makes an individual highly susceptible to infections.
In alpha 1-antitrypsin deficiency----the important neutrophil enzyme elastase is not
adequately inhibited by alpha 1-antitrypsin, leading to excessive tissue damage
in the presence of inflammation – the most prominent one being pulmonary
emphysema.

In Familial Mediterranean fever (FMF)-- mutation in the pyrin (or marenostrin)

gene--- expressed mainly in neutrophil granulocytes---leads to a constitutively
active acute-phase response and causes attacks of fever, arthralgia, peritonitis,
and – eventually – amyloidosis.
5. Eosinophils
- kill invading parasites
- Along with mast cells, they also control mechanisms associated with
allergy and asthma.
- express Fc receptors for IgG (CD32).
* role in adaptive immunity---produce IL-5--w/c recruits Ig-specific
antibody responses
* Eosinophilia- An increase in eosinophils (presence of more than 500
eosinophils/microlitre of blood)
- typically seen in people with a parasitic infestation of the
intestines, collagen vascular disease (such as rheumatoid arthritis),
malignant diseases such as Hodgkin's disease, extensive skin
diseases (such as exfoliative dermatitis) etc.
6. Basophil and mast cells
- release TNF-α ,IL-6 IFN-ϒ in response to a variety of bacterial
PAMPs

*** role in adaptive immunity

--- produce IL-4---w/c recruits T 2 Helper T cell responses and
recruit IgG1 and IgE - specific antibody responses.
 The Complement System
- helps or “complements” the ability of antibodies and phagocytic
cells to clear pathogens from an organism
- a series of plasma enzymes,regulatory proteins, and proteins that
are activated in a cascading fashion---resulting in cell lysis.
-basic functions of complement:
1.Opsonization - enhancing phagocytosis of antigens
2.Chemotaxis - attracting macrophages and neutrophils
3.Cell Lysis - rupturing membranes of foreign cells
4.Agglutination- clustering and binding of pathogens together
(sticking)

*** serine proteases---series of enzymes of the complement system.

CYTOKINES

- serve as molecular messengers between cells.

- are proteins that are produced by cells and interact with cells of the
immune system in order to regulate the body's response to
disease and infection.
- also mediate normal cellular processes in the body.
- are released by cells into the circulation or directly into tissue. The
cytokines locate target immune cells and interact with receptors
on the target immune cells by binding to them. The interaction
triggers or stimulates specific responses by the target cells.
-Overproduction or inappropriate production of certain cytokines by
the body can result in disease.
***e.g. , it has been found that interleukin-1 (IL-1) and tumor
necrosis factor-alpha (TNF-alpha) are produced in excess in
rheumatoid arthritis where they are involved in inflammation
and tissue destruction.
 ADAPTIVE IMMUNTY
* develops when innate immunity is ineffective in eliminating
infectious agents and the infection established.
- primary functions:
a) recognition of specific “non-self” antigens in the presence of
“self” antigens;
b) the generation of pathogen-specific immunologic effector
pathways that eliminate specific pathogens or pathogen infected cells
c) the development of an immunologic memory that can quickly
eliminate a specific pathogen should subsequent infections occur.

- The cells of the adaptive immune system include:

---T cells, which are activated through the action of antigen
presenting cells (APCs)
--- B cells
 T cells

- arise in the bone marrow BUT migrate to the thymus gland to mature
-cannot recognize antigen alone, T-cell receptors can recognize only
antigen bound to cell-membrane proteins (MHC molecules)
---- CD4-TH; CD8-TC
- TYPES: Helper T cells, Cytotoxic T cells, Suppressor T cells
- CRUCIAL STEPS:
--a naive T cell encounters antigen combined with a MHC
molecule on a cell
--T cell proliferates
-- differentiates into memory T cells and various effector T cells
 B CELLS

-B lymphocytes mature
within the bone marrow;
when they leave it, each
expresses a unique antigen binding
receptor on its membrane
- production of antibodies against
foreign antigens
- memory B cells--long lived and
continue to express Ag-binding
receptors.
- plasma cells--short livedand do not
express Ag-binding receptors.
 T-cell receptors (TCRs) enable the cell to bind to and, if additional
signals are present, to be activated by and respond to an epitope
presented by APCs
 There are two types of T cells and thus two types of TCRs: CD8 and CD4
- CD8 T cells destroy the cells they bind to, such as virus cells.
- CD4 T cells group together to cause inflammation, which isolates an
infected area so it can heal = helps build immunities

 B-cell receptors (BCRs) enable the cell to bind to and, if additional

signals are present, to be activated by and respond to an epitope on
molecules of a soluble antigen

---B cells bind to these toxins and digest them into smaller pieces

---the response ends with descendants of the B cell secretingantibodies (via the
plasma cells)
• B cells-- antibody production
- play a role in the humoral or antibody-mediated immune
response
* 5 Types of antibodies
 Passive vs Active Immunization
***acquired immunity - attained--
passive or active immunization.

* Passive immunization--
transfer of active humoral
immunity in te form of
"ready-made Abs" from one
individual to another.
-- can occur naturally by
transplacental transfer of
maternal antibodies to
developing fetus.
-- induced artificially by
injecting a recipient w/
exogenous Abs targeted to a
specific pathogen or toxin.
* Active immunization
- production of Abs against a
specific agent after exposure
to the Ag.
- acquired through either natural
infection w/ a microbe or
through vaccines that consist
of attenuated(weakened)
pathogens or inactivated
organisms.
 Immune Tolerance
- A state of unresponsiveness to a specific antigen or group of
antigens to which a person is normally responsive.
- defined as a state in which a T cell can no longer respond to antigen.
The T cell "tolerates" the antigen.
- achieved under conditions that suppress the immune reaction and is
not just the absence of a immune response.
- Immune tolerance can result from a number of causes including:
 Prior contact with the same antigen in fetal life or in the newborn period
when the immune system is not yet mature
 Prior contact with the antigen in extremely high or low doses
 Exposure to radiation, chemotherapy drugs, or other agents that impair
the immune system
 Heritable diseases of the immune system
 Acquired diseases of the immune system such as HIV/AIDS
Autoimmunity - involves the loss of normal immune homeostasis such that the
organism produces an abnormal response to its own tissue.
- hallmark: presence of self-reactive T cells,autoantibodies and inflammation.
Autoimmune diseases
- syndromes caused by the activation of T or B cells or both---with no evidence of
other causes such as infection or malignancies.
- most are caused by combination of of excess T nd B cell reactivity.

*** Multiple factors contribute to the genesis of clinical autoimmune

disease syndromes:
1.genetic susceptibility
2. environmental immune stimulants such as drugs [e.g., procainamide and
phenytoin (Dilantin) with drug-induced systemic lupus erythematosus],
3. infectious agent triggers (such as Epstein-Barr virus and autoantibody
production against red blood cells and platelets),
4. loss of T regulatory cells (leading to thyroiditis, adrenalitis, and oophoritis).
 Mechanisms of Immune-mediated damage to microbes
or host tissues
* classic weapons of the adaptive immune system (T cells, B cells)
interface with cells (macrophages, dendritic cells, NK cells,
neutrophils, eosinophils, basophils) and soluble products
(microbial peptides, pentraxins, complement and coagulation
systems) of the innate immune system.

 five general phases of host defenses:

1) migration of leukocytes to sites of antigen localization
2) antigen-nonspecific recognition of pathogens by macrophages and
other cells and systems of the innate immune system
3) specific recognition of foreign antigens mediated by T and B
lymphocytes
(4) amplification of the inflammatory response with recruitment of
specific and nonspecific effector cells by complement components,
cytokines, kinins, arachidonic acid metabolites, and mast cell-
basophil products

5) macrophage, neutrophil, and lymphocyte participation in

destruction of antigen with ultimate removal of antigen particles by
phagocytosis (by macrophages or neutrophils)
or by direct cytotoxic mechanisms (involving macrophages,
neutrophils, DCs, and lymphocytes)
The Molecular Basis of Lymphocyte-Endothelial
Cell Interactions
 The control of lymphocyte circulatory patterns between the
bloodstream and peripheral lymphoid organs operates at the level
of lymphocyte-endothelial cell interactions to control the
specificity of lymphocyte subset entry into organs.
 second stage
 Lymphocyte homing to peripheral lymph nodes involves
adhesion of L-selectin to glycoprotein HEV ligands collectively
referred to as peripheral node addressin (PNAd), whereas homing
of lymphocytes to intestine Peyer’s patches primarily involves
adhesion of the a4,ß7 integrin to mucosal addressin cell adhesion
molecule-1 (MAdCAM-1) on the Peyer’s patch HEVs.
However, for migration to mucosal Peyer’s patch lymphoid
aggregates, naïve lymphocytes primarily use l-selectin,
whereas memory lymphocytes use α4,β7 integrin.

***α4,β1 Integrin (CD49d/CD29, VLA-4)–VCAM-1

interactions are important in the initial interaction
of memory lymphocytes with HEVs of multiple
organs in sites of inflammation